The Reactive Oxygen Species in Macrophage Polarization: Reflecting Its Dual Role in Progression and Treatment of Human Diseases

Abstract

High heterogeneity of macrophage is associated with its functions in polarization to different functional phenotypes depending on environmental cues. Macrophages remain in balanced state in healthy subject and thus macrophage polarization may be crucial in determining the tissue fate. The two distinct populations, classically M1 and alternatively M2 activated, representing the opposing ends of the full activation spectrum, have been extensively studied for their associations with several disease progressions. Accumulating evidences have postulated that the redox signalling has implication in macrophage polarization and the key roles of M1 and M2 macrophages in tissue environment have provided the clue for the reasons of ROS abundance in certain phenotype. M1 macrophages majorly clearing the pathogens and ROS may be crucial for the regulation of M1 phenotype, whereas M2 macrophages resolve inflammation which favours oxidative metabolism. Therefore how ROS play its role in maintaining the homeostatic functions of macrophage and in particular macrophage polarization will be reviewed here. We also review the biology of macrophage polarization and the disturbance of M1/M2 balance in human diseases. The potential therapeutic opportunities targeting ROS will also be discussed, hoping to provide insights for development of target-specific delivery system or immunomodulatory antioxidant for the treatment of ROS-related diseases.

Figure 1

Involvement of ROS in regulating M1 responsible phagocytic activity and inflammatory response. (a) Multiple pathways are involved in generating NADPH, followed by ROS production by NADPH oxidase. The high ROS level mainly used to mediate the phagocytic activity of M1 macrophages. (b) ROS serves as second messenger mediating the inflammatory response of M1 macrophages, primarily through MAPK and NF-κB as well as inflammasome activation. Mt, mitochondrial; FA, fatty acid; G6P, glucose-6-phosphate; R5P, ribulose-5-phosphate; PPP, pentose phosphate pathway; TCA, tricarboxylic acid cycle.

Figure 2

Involvement of ROS in regulating M2 responsible inflammation resolving and wound healing activities. Multiple pathways are involved in reducing NADPH and its oxidase followed by reduced ROS generation. The low ROS level was accompanied by reduced inflammatory mediators; increased M2-regulated genes responsible for inflammation resolution; and increased disulphide protein degradation which enhanced wound healing effect of M2. S7P, sedoheptulose-7-phosphate; sedo, sedoheptulose; PPP, pentose phosphate pathway; SYNCRIP, synaptotagmin binding, cytoplasmic RNA interacting protein; SOD, superoxide dismutase.